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BR-112020022114-B1 - Tetrazole compound containing inhibitors of apoptosis signaling kinase-1, pharmaceutical composition and uses thereof.

BR112020022114B1BR 112020022114 B1BR112020022114 B1BR 112020022114B1BR-112020022114-B1

Abstract

The present invention discloses the compounds of Formula (I), and pharmaceutically acceptable salts and esters thereof, which inhibit apoptosis signaling regulator kinase 1 (ASK-1), which is associated with autoimmune disorders, neurodegenerative disorders, inflammatory diseases, chronic kidney disease, and cardiovascular disease. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to an individual suffering from ASK-1-related disease. The present invention also relates to methods of treating an ASK-1-related disease in an individual by administering a pharmaceutical composition comprising the compounds of the present invention. The present invention specifically relates to methods of treating ASK-1 associated with hepatic steatosis, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

Inventors

  • Guoqiang Wang
  • YAT SUN OR
  • Ruichao Shen
  • Brett Granger
  • Jing He
  • Xuechao Xing
  • Yong He
  • Jiang Long
  • Jun Ma
  • Bin Wang

Assignees

  • ENANTA PHARMACEUTICALS, INC

Dates

Publication Date
20260310
Application Date
20190501
Priority Date
20180502

Claims (19)

  1. 1. Compound, characterized by the fact that it has Formula 1: or a pharmaceutically acceptable salt thereof, wherein: It is selected from the groups below: R1 is selected from the group consisting of: 1) hydrogen; 2) optionally substituted C1-C8 alkyl; 3) optionally substituted C2-C8 alkenyl; 4) optionally substituted C2-C8 alkynyl; 5) optionally substituted C3-C8 cycloalkyl; 6) optionally substituted aryl; 7) optionally substituted arylalkyl; 8) optionally substituted 3- to 8-membered heterocycloalkyl; 9) optionally substituted heteroaryl; and 10) optionally substituted heteroarylalkyl; R2 is X is N or C-R3; R3 is selected from the group consisting of: 1) hydrogen; 2) halogen; 3) optionally substituted C1-C8 alkyl; and 4) optionally substituted C1-C8 alkoxyl; 5) is selected from the group consisting of: 1) hydrogen; 2) halogen; 3) optionally substituted C1-C8 alkyl; 4) optionally substituted C2-C8 alkenyl; 5) optionally substituted C2-C8 alkynyl; 6) optionally substituted C3-C8 cycloalkyl; 7) optionally substituted aryl; 8) optionally substituted arylalkyl; 9) optionally substituted 3- to 8-membered heterocycloalkyl; 10) optionally substituted heteroaryl; 11) optionally substituted heteroarylalkyl; e12) -N(R5)(R6); wherein R5 and R6 are independently selected from the group consisting of hydrogen, -C1-C8 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein the -C1-C8 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are substituted with 0 to 3 substituents independently selected from halo, alkyl, alkylamino, dialkylamino, alkylC(O)NH-, arylC(O)NH-, heteroarylC(O)NH-, -CN, alkoxy, -CF3, aryl and heteroaryl; alternatively, R5 and R6 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycle; and wherein the term “substituted” refers to the independent substitution of one or more of the hydrogen atoms by substituents independently selected from halo; -C1-C4 alkyl; halo-C1-C4-alkyl; -C2-C4 alkenyl; halo-C2-C4-alkenyl; -C3-C6 cycloalkyl; -C1-C4 alkoxy; -halo-C1-C4-alkoxy; -CN; - OH; NH2; -C1-C4 alkylamino; di(C1-C4-alkyl)amino; and NO2.
  2. 2. Pharmaceutically acceptable compound or salt thereof according to claim 1, characterized in that it has one of the Formulas (II-a), (II-c), (II-e) or (II-g): in which R2 and R4 are as defined in claim 1.
  3. 3. Pharmaceutically acceptable compound or salt thereof according to claim 1, characterized in that it has one of Formulas (III-a) to (III-n): where R1, R2 and R4 are as defined in claim 1.
  4. 4. Pharmaceutically acceptable compound or salt thereof according to claim 1, characterized in that it has one of Formulas (IV-a) to (IV-n): where R1, R2 and R4 are as defined in claim 1.
  5. 5. A pharmaceutically acceptable compound or salt thereof according to claim 1, characterized in that it is selected from the following compounds:
  6. 6. A pharmaceutically acceptable compound or salt thereof according to claim 5, characterized in that it has the formula
  7. 7. A pharmaceutically acceptable compound or salt thereof according to claim 5, characterized in that it has the formula
  8. 8. Pharmaceutical composition, characterized in that it comprises a compound defined in any one of claims 1 to 7 and a pharmaceutically acceptable carrier or excipient.
  9. 9. Use of a compound defined in any one of claims 1 to 7, characterized in that it is for the manufacture of a medicament for the treatment of an ASK-1-mediated disease or condition in an individual in need thereof.
  10. 10. Use according to claim 9, characterized in that the ASK-1-mediated disease or condition is selected from the group consisting of an autoimmune disorder, a neurodegenerative disorder, an inflammatory disease, chronic kidney disease, renal disease, cardiovascular disease, a metabolic disease, or an acute or chronic liver disease.
  11. 11. Use according to claim 9, characterized in that the disease or condition mediated by ASK-1 is a chronic liver disease selected from the group consisting of primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, cholestasis associated with parenteral nutrition (PNAC), cholestasis associated with bacterial overgrowth or sepsis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), graft-versus-host disease associated with liver transplantation, liver regeneration from living donor transplantation, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjögren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis or alpha 1-antitrypsin deficiency.
  12. 12. Use according to claim 9, characterized in that the disease or condition mediated by ASK-1 is a kidney disease selected from the group consisting of diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, renal fibrosis, and polycystic kidney disease.
  13. 13. Use according to claim 9, characterized in that the disease or condition mediated by ASK-1 is a cardiovascular disease selected from the group consisting of atherosclerosis, arteriosclerosis, ischemia/reperfusion in stroke, cardiac hypertrophy, respiratory diseases, heart attacks and myocardial ischemia.
  14. 14. Use according to claim 9, characterized in that the disease or condition mediated by ASK-1 is a metabolic disease selected from the group consisting of insulin resistance, Type I and Type II diabetes, and obesity.
  15. 15. Use according to claim 9, characterized in that the disease or condition mediated by ASK-1 is a chronic kidney disease selected from the group consisting of polycystic kidney disease, pyelonephritis, renal fibrosis, and glomerulonephritis.
  16. 16. Use of a compound defined in any one of claims 1 to 7, characterized in that it is for the preparation of a medicament to treat a disease selected from the group consisting of glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, multiple sclerosis or Sjögren's syndrome in an individual in need thereof.
  17. 17. Use of a compound defined in any one of claims 1 to 7, characterized in that it is for the preparation of a medicament to treat a disease selected from the group consisting of ischemia/reperfusion in stroke, heart attacks, myocardial ischemia, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, hepatic ischemia, congestive heart failure, pathological immune responses, such as those caused by T cell activation and thrombin-induced platelet aggregation in an individual in need thereof.
  18. 18. Use of a compound defined in any one of claims 1 to 7, characterized in that it is for the preparation of a medicament to treat a disease selected from the group consisting of osteoporosis, osteoarthritis and bone disorder related to multiple myeloma in an individual in need thereof.
  19. 19. Use of a compound defined in any one of claims 1 to 7, characterized in that it is for the preparation of a medicament to treat a disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), epilepsy, seizures, Huntington's disease, polyglutamic diseases, traumatic brain injury, ischemic and hemorrhagic stroke, cerebral ischemia or neurodegenerative disease, including apoptosis-induced neurodegenerative disease, caused by traumatic injury, acute hypoxia, ischemia or glutamate neurotoxicity in an individual in need thereof.

Description

RELATED ORDERS [001] This application claims the benefit of Provisional Application No. U.S. 62/665,789 filed May 2, 2018. All teachings of the above application are incorporated herein by reference. TECHNICAL FIELD [002] The present invention generally relates to pharmaceutical compounds and compositions useful as ASK-1 inhibitors. Specifically, the present invention relates to compounds useful as ASK-1 inhibitors and methods for their preparation and use. BACKGROUND OF THE INVENTION [003] Apoptosis signal regulator kinase 1 (ASK-1) is a member of the mitogen-activated protein kinase kinase kinase (MAPKKK, MAPK3) family, which, when activated, phosphorylates downstream MAP kinase kinase (MAPKK, MAP2K), which in turn activates MAP kinases (MAPK). MAPKs induce a response through phosphorylation of cellular substrates, thereby regulating the activity of transcription factors that ultimately control gene expression. Specifically, ASK-1, also known as MAPKKK5, phosphorylates MAPKK4/MAPKK7 or MAPKK3/MAPKK6, which subsequently phosphorylates and activates c-Jun N-terminal protein kinase (JNK) and p38 MAPKs, respectively (H. Ichijo, et al., Cell Comm. Signal 2009, 7, 1-10; K. Takeda, et al., Annu. Rev. Pharmacol. Toxicol. 2008, 48, 199-225; H. Nagai, et al., J. Biochem. Mol. Biol. 2007, 40, 1-6). Activation of JNK and p38 pathways triggers a downstream stress response, such as apoptosis, inflammation, or differentiation (H. Ichijo, et al., Science 1997, 275, 90-94; K. Takeda, et al., J. Biol. Chem. 2000, 275, 9805-9813; K. Tobiume, et al., EMBO Rep. 2001, 2, 222-228; K. Sayama et al., J. Biol. Chem. 2001, 276, 999-1004). [004] ASK-1 activity is regulated by thioredoxin (Trx), which binds to the N-terminal end of ASK-1 (M. Saitoh, et al., EMBO J. 1998, 17, 2596 to 2606). ASK-1 is activated after autophosphorylation at Thr838 in response to environmental stimuli including oxidative stress, lipopolysaccharides (LPS), reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, an increase in cellular calcium ion concentrations, Fas ligand, and various cytokines such as tumor necrosis factor (TNF) (H. Nishitoh, et al., Genes Dev. 2002, 16, 1345-1355; K. Takeda, et al., EMBO Rep. 2004, 5, 161-166; A. Matsuzawa, et al., Nat. Immunol. 2005, 6, 587-592). [005] ASK-1 was associated with autoimmune disorders, neurodegenerative disorders, inflammatory diseases, chronic kidney disease, cardiovascular disease, metabolic disorders, and acute and chronic liver diseases (R. Hayakawa, et al., Proc. Jpn. Acad., Ser. B 2012, 88, 434 to 453). [006] More specifically, ASK-1 was associated with hepatic steatosis, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). In a mouse model, high-fat diets induced hepatic steatosis, ultimately leading to fat accumulation and fatty acid oxidation. This leads to the generation of ROS which caused hepatocyte dysfunction and death (S. K. Mantena, et al., Free Radic. Biol. Med. 2008, 44, 1259-1272; S. K. Mantena, et al., Biochem. J. 2009, 417, 183-193). Furthermore, TNF has been shown to be critical for hepatocyte apoptosis via the ASK-1-JNK pathway, and TNF-deficient mice showed reduced hepatic steatosis and fibrosis (W. Zhang, et al., Biochem. Biophys. Res. Commun. 2010, 391, 1731-1736). [007] Small molecule compounds that act as ASK-1 inhibitors have been disclosed in the following publications: documents WO 2008/016131, WO 2009/027283, WO 2009/0318425, WO 2009/123986, US 2009/0318425, WO 2011/041293, WO 2011/097079, US 2011/0009410, G.P. Volynets, et al., J. Med. Chem. 2011, 54, 2680 to 2686, WO 2012/003387, WO 2012/011548, WO 2012/080735, Y. Terao, et al., Bioorg. Med. Chem. Lett. 2012, 22, 7326 to 7329, WO 2013/112741, G.P. Volynets, et al., Eur. J. Med. Chem. 2013, 16, 104 to 115, US 2014/0018370, WO 2014/100541, WO 2015/095059, WO 2016/049069, WO 2016/049070, WO 2018/090869, WO 2018/133865, WO 2018/133866, WO2018/148204, WO 2018/149284, WO 2018/151830, WO/2018/157856, WO 2018/157857, WO 2018/160406, WO 2018/169742, WO 2018/183122, WO2018/187506, WO 2018/209354, WO 2018/218042, WO 2018/218044, WO2018/218051, WO 2018/233553, US 2019/0062310, WO 2019/070742, WO2019/050794, WO 2019/051265 and WO 2019/034096. [008] There is a need for the development of ASK-1 inhibitors for the treatment and prevention of disease. SUMMARY OF THE INVENTION [009] The present invention relates to pharmaceutical compounds and compositions useful as ASK-1 inhibitors. Specifically, the present invention relates to compounds useful as ASK-1 inhibitors and methods for their preparation and use. In addition, the present invention includes the process for preparing said compounds. [010] In its main aspect, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or ester thereof: [011] in which [012] is optionally substituted aryl or optionally substituted heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, provided that